To investigate the therapeutic implications of the current paradigm that autoimmune disease can result from defects in the clearance of dying/apoptotic cells, we have conducted preliminary studies that have shown that infusions of a natural antibody derived from innate-like B cells can greatly improve the survival of lupus- prone mice. We believe that these findings reflect the properties of a larger class of natural antibodies with common immunobiologic properties that derive from their self-reactive specificities, and by affecting other facets of the innate and adaptive immune system these antibodies can ameliorate or prevent autoimmune pathogenesis. To advance these studies, we will further characterize the properties of these antibodies, and investigate their roles in immunoregulation. We will assess whether the protective properties of specific natural antibodies are linked to binding specificities for neo-determinants on oxidized phospholipids that enable the recognition of apoptosis-associated epitopes, and whether such antibody autospecificities convey enhanced phagocytosis of dying cells. Non-autoimmune and well-defined lupus models will also be used to elucidate the molecular and cellular mechanisms by which such antibody treatments protect from the initiation and/or progression of autoimmune pathogenesis, which includes lupus nephritis and autoimmune cytopenias. These studies will dissect the effects of such antibody treatments on the co-stimulatory properties of mononuclear cells, with a special interest in determining whether treatments can recruit immunomodulatory dendritic cells. Based on interim findings, we will directly test mechanistic hypotheses using engineered antibody variants predicted to have enhanced protective properties and assay their in vivo activities. To determine the clinical relevance of these findings, we will evaluate the profile of natural and pathologic autoantibody responses in clinical populations, including close siblings and sets of monozygotic and dizygotic twins with lupus and other autoimmune diseases. These studies will test the hypothesis that clinical disease in individuals with inherited genetic susceptibility to autoimmune disease (in)directly correlates with levels of natural antibodies of autospecificities, which are postulated to provide protective properties. Together, these important investigations will test paradigm-shifting hypotheses regarding the functional roles of the products of innate-like B cells and their contributions to homeostatic pathways that protect the host. These studies are relevant to the mission of the agency as the results should lead to the development of new therapeutic approaches that provide benefits to many individuals with diverse types of chronic inflammatory, degenerative and autoimmune diseases, which affect their blood cells, kidneys, blood vessels, joints or other major organs.